PROJECT 4: INTRAVENOUS IMMUNOGLOBULIN (IVIG) FOR TREATMENT OF ALZHEIMER'S DISEASE Antibodies against the amyloid beta (Ap) protein have demonstrated a remarkable ability to arrest and even reverse key elements of the neuropathology of Alzheimer's Disease (AD). Unfortunately, attempts to treat AD by active vaccination failed to generate anti-A(3 antibodies in a majority of patients and caused severe brain inflammation in others. Passive immunization (administration of antibodies from an exogenous source) can more consistently deliver therapeutic antibodies while avoiding many of the safety and tolerability issues associated with active vaccination. Intravenous Immunoglobulin (IVIg) is a very promising agent for this purpose. IVIg is a purified human immunoglobulin preparation with unique immune-modulating properties that was recently found to contain elevated titers of polyclonal anti-Ap antibodies. IVIg's established safety record from over 25 years of clinical use as an FDA-approved treatment for immune deficiency and autoimmune disorders will reduce the time and risks associated with testing in AD. In three pilot studies in mild to moderate stage AD to date, IVIg treatment for six to twelve months significantly improved dementia symptoms and was generally well-tolerated. In addition, IVIg increased plasma anti-Ap antibody titers and promoted clearance of Ap from the cerebrospinal fluid. An ongoing Phase II study will provide further information about IVIg's pharmacokinetic profile and mechanisms of action. A large scale, controlled, prospective clinical trial is needed to determine whether IVIg is useful for treating AD. To meet this need, we will carry out a 30-week placebo-controlled, double-blind, randomized, multi-center Phase III clinical trial examining whether IVIg is effective and well-tolerated for treating mild to moderate AD. A total of 210 probable AD patients will be randomly assigned to receive intravenous infusions of either IVIg 0.4g/kg or a physiologic saline solution every two weeks for six months. Outcome will be evaluated at baseline, after 12 and 24 weeks of treatment and six weeks after the final infusion. The primary outcome measures will be the mean change from baseline to 24 weeks on the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog) and the ADCS-Clinical Global Impression of Change (ADCS-CGIC). Levels of Ap protein and anti-Ap antibody titers in plasma will be measured at four time points to test for possible correlation with IVIg treatment. Other secondary outcome measures include the Neuropsychiatric Inventory as a measure of behavioral change, the ADCS-Activities of Daily Living scale to assess functional status and the ADCS Pharmacoeconomic Inventory as an index of cost-effectiveness. Compliance and adverse events will be carefully monitored throughout the trial. This study has been powered to provide an 80-90% likelihood of detecting significant differences in the primary outcome measures after six months of double-blind treatment.